This application relates to compositions comprising oligosaccharide aldonic acids and related compounds, and their use for cosmetic and dermatological indications, reducing and soothing mucosa and skin erythema, inflammation or reaction caused by internal or external factors, wound healing, and care of skin, hair, nail, and oral and vaginal mucosa, including the use for changes associated with intrinsic and extrinsic aging, and changes or damage caused by extrinsic factors such as sunlight, radiation, air pollution, wind, cold, heat, dampness, chemicals, smoke, and cigarette smoking.
In our U.S. patent application Ser. No. 06/945,680, filed Dec. 23, 1986, entitled xe2x80x9cAdditives Enhancing Topical Actions of Therapeutic Agents, xe2x80x9d and related applications, issuing, inter alia, as U.S. Pat. Nos. 5,665,776, 5,389,677, and 5,422,370, we described and claimed compositions for and methods of enhancing the therapeutic effect of a cosmetic or pharmaceutical agent by using a hydroxyacid in combination with the agent. The generic structure of hydroxymonocarboxylic acids disclosed may appear similar to the one described herein for oligosaccharaide aldonic acids. The location of the R2 molecule is a notable difference. This application disclosed that xe2x80x9cwhen n=0 and m=1 or more, the hydroxymonocarboxylic acid is also called aldonic acid. The name comes from a carbohydrate, aldose, which may be oxidized to aldonic acid by the oxidation of the aldehyde group in aldose to the carboxylic group.xe2x80x9d The application, however, does not disclose or suggest that a carbohydrate may be chemically linked to an aldonic acid. Thus, this application does not disclose or suggest oligosaccharide aldonic acids.
In our related U.S. patent application Ser. No. 07/683,437, filed Apr. 10, 1991, entitled xe2x80x9cCompositions Comprising 2-Hydroxycarboxylic Acids and Related Compounds, and Methods for Alleviating the Signs of Dermatological Aging,xe2x80x9d and related applications, and issuing, inter alia, as U.S. Pat. Nos. 5,547,988, 5,554,597, and 5,561,158, we described and claimed the use of topical compositions containing a 2-hydroxycarboxylic acid or related compound for use in alleviating or improving the signs of aging, including the signs caused by intrinsic and extrinsic aging or extrinsic factors, of the skin, hair and nails. Among the many compounds disclosed in this application, lactobionic acid, an oligosaccharide aldonic acid, is listed as a useful related compound.
We have now discovered that oligosaccharide aldonic acids and related compounds, as a group, provide numerous benefits in the treatment and prevention of various cosmetic conditions and dermatological disorders, including those associated with intrinsic and extrinsic aging, as well as changes and damage caused by extrinsic factors. Oligosaccharide aldonic acids and related compounds also provide numerous benefits in the treatment of skin wounds; reducing or soothing erythema, inflammation or irritation; general care, as well as treatment and prevention of diseases and conditions, of the nasal, oral and vaginal mucosa; and general oral care and treatment and prevention of oral and gum diseases.
We have further discovered that oligosaccharide aldonic acids possess unexpected physicochemical properties, including binding with water and the formation of a gel matrix with water. In addition, the oligosaccharaide aldonic acids disclosed herein are antioxidant substances. Moreover, beneficial effects from an oligosaccharaide aldonic acid within the skin, nail and hair are expected to include those provided by glycosaminoglycans (GAGs). This is due to similarities in the basic chemical structure of oligosaccharaide aldonic acids and GAGs, and the fact that they both form a gel matrix with water. Exemplary beneficial effects and functions of GAGs inside the skin includes (i) binding with polycations and cations, such as sodium and potassium ions, to enhance water retention, and (ii) specific interaction with collagen, elastin, fibronectin, laminin and other proteins to stabilize the turgor of the skin.
Accordingly, it is an object of this invention to provide methods and compositions which are useful in the treatment and prevention of certain cosmetic conditions and dermatological disorders, promote wound healing, and are useful for general care of skin, hair, nail, oral and vaginal mucosa, and oral and gum diseases.
We have now discovered that oligosaccharide aldonic acids have protective as well as healing effects for skin, hair, nail; oral, nasal and vaginal mucosa. The oligosaccharide aldonic acids include glycerbionic acids, erythrobionic acids, threobionic acids, ribobionic acids, arabinobionic acids, xylobionic acids, lyxobionic acids, allobionic acids, altrobionic acids, glucobionic acids, mannobionic acids, gulobionic acids, idobionic acids, galactobionic acids, talobionic acids, alloheptobionic acids, altroheptobionic acids, glucoheptobionic acids, mannoheptobionic acids, guloheptobionic acids, idoheptobionic acids, galactoheptobionic acids and taloheptobionic acids.
Compositions comprising oligosaccharide aldonic acids are beneficial and effective for general care, reducing and soothing mucosa and skin erythema, inflammation or reaction caused by internal or external factors, treatment and healing of skin, hair, nail; nasal, oral and vaginal mucosa including treatment, healing and prevention of cosmetic conditions and dermatological indications as well as cosmetic and clinical signs of changes associated with intrinsic aging, or the damages caused by extrinsic factors as sunlight, radiations, air pollution, wind, cold, dampness, heat, chemicals, smoke, and cigarette smoking.
General care, reducing and soothing mucosa and skin erythema, inflammation or irritation caused by internal or external factors, treatment and healing of skin, hair, nail; nasal, oral and vaginal mucosa, and treatment, healing and prevention of cosmetic conditions and dermatological indications as well as cosmetic and clinical signs of changes associated with intrinsic aging, or the damages caused by extrinsic factors as sunlight, radiations, air pollution, wind, cold, dampness, heat, chemicals, smoke, and cigarette smoking may include blemished, irritated, inflamed, unhealthy, damaged or abnormal mucosa, skin, hair, nail, nostril, ear canal or vaginal conditions; oral or gum disease; disturbed keratinization; defective syntheses or repair of dermal components, and changes associated with intrinsic and extrinsic aging of skin, nail and hair. Those conditions and indications include dryness of the skin, nail and hair; xerosis; ichthyosis; palmar and plantar hyperkeratoses; uneven and rough surface of skin, nail and hair; dandruff; Darier""s disease; lichen simplex chronicus; keratoses; acne; pseudofolliculitis barbae; eczema; psoriasis; pruritus; warts; herpes; age spots; lentigines; melasmas; blemished skin; mottled skin; hyperkeratoses; hyperpigmented skin; abnormal or diminished syntheses of collagen, glycosaminoglycans, proteoglycans and elastin as well as diminished levels of such components in the dermis; cellulite; stretch marks; skin lines; fine lines; wrinkles; thinning of skin, nail plate and hair; skin thickening due to elastosis of photoaging, loss or reduction of skin, nail and hair resiliency, elasticity and recoilability; lack of skin, nail and hair lubricants and luster; dull and older-looking skin, nail and hair; fragility and splitting of nail and hair.
Oligosaccharide aldonic acids are also beneficial for wound healing of skin; irritated or inflamed mucosa or skin; for skin lightening; for cleansing of skin, hair and nail; for conditioning of skin and nail; for protection from extrinsic factors; for mouthwashes; for use as antioxidant agent, toner, cleanser, moisturizer, emollient, protectant, foundation makeup, beauty masks, face powders, rouge, cover up, lipsticks, eye makeup, dentifrices, mouthwashes, suntan preparation, soap preparation, and other topical preparations.
1. Oligosaccharaide Aldonic Acids and Related Compounds
An oligosaccharide aldonic acid may be defined as an aldonic acid having a carbohydrate chemically linked to the aldonic acid. The total number of carbohydrate monomers including the aldonic acid itself ranges from 2 to 10. The aldonic acid may be described as an oxidized form of a carbohydrate. For example, gluconic acid may be obtained from glucose through an oxidation of the aldehyde group to a carboxylic group. Although an oligosaccharide aldonic acid may consist of one to ten aldonic acid units, preferred compounds contain one aldonic acid unit and one to nine carbohydrate monomers. When the total number of the carbohydrate monomers including the aldonic acid itself are 2, 3, 4, 5, 6, 7, 8, 9 and 10, these oligosaccharide aldonic acids may be respectively called aldobionic acid, aldotrionic acid, aldotetraonic acid, aldopentaonic acid, aldohexaonic acid, aldoheptaonic acid, aldooctaonic acid, aldononaonic acid and aldodecaonic acid. The most preferred is aldobionic acid. If the name of a precursor oligosaccharide is known, such name may be utilized as a prefix. For example, lactobionic acid is derived from lactose, maltobionic acid from maltose, cellobionic acid from cellobiose, isomaltobionic acid from isomaltose, gentiobionic acid from gentiobiose and laminarabionic acid from laminarabiose. Alternatively, the name of a specific aldonic acid may also be used such as glycerbionic acid, erythrobionic acid, xylobionic acid, mannobionic acid and glucoheptabionic acid.
The smallest aldonic acid having three carbon atoms is glyceric acid, which is obtained from glyceraldehyde. A carbohydrate having one to nine monomers may be chemically linked to one of the two hydroxyl groups at 2nd or 3rd carbon position of glyceric acid to form an oligosaccharide aldonic acid. When one carbohydrate monomer is linked to glyceric acid the compound may be called glycerbionic acid.
Erythronic acid and threonic acid, which have four carbon atoms, may be obtained respectively from erythrose and threose through an oxidation process. A carbohydrate having one to nine monomers may be chemically linked to one of the three hydroxyl groups at 2nd, 3rd or 4th carbon position of the aldonic acid. When one carbohydrate monomer is attached to the aldonic acid the resulting compound may be called erythrobionic acid or threobionic acid.
Ribonic acid, arabinoic acid, xylonic acid and lyxonic acid, which have five carbon atoms, may be obtained respectively from ribose, arabinose, xylose and lyxose through an oxidation process. A carbohydrate having one to nine monomers may be chemically linked to one of the four hydroxyl groups at 2nd, 3rd, 4th or 5th carbon position of the aldonic acid. When one carbohydrate monomer is attached to the aldonic acid, the resulting compound may be called ribobionic acid, arabinobionic acid, xylobionic acid or lyxobionic acid.
Allonic acid, altronic acid, gluconic acid, mannonic acid, gulonic acid, idonic acid, galactonic acid and talonic acid, which have six carbon atoms, may be obtained respectively from allose, altrose, glucose, mannose, gulose, idose, galactose and talose through oxidation. A carbohydrate having one to nine monomers may be chemically linked to one of the five hydroxyl groups at 2nd, 3rd, 4th, 5th or 6th carbon position of the aldonic acid. When one carbohydrate monomer is attached to the aldonic acid, the resulting compound may be called allobionic acid, altrobionic acid, glucobionic acid, mannobionic acid, gulobionic acid, idobionic acid, galactobionic acid or talobionic acid.
Alloheptonic acid, altroheptonic acid, glucoheptonic acid, mannoheptonic acid, guloheptonic acid, idoheptonic acid, galactoheptonic acid and taloheptonic acid, which have seven carbon atoms, may be obtained respectively from alloheptose, altroheptose, glucoheptose, mannoheptose, guloheptose, idoheptose, galactoheptose and taloheptose through oxidation. A carbohydrate having one to nine monomers may be chemically linked to one of the six hydroxyl groups at 2nd, 3rd, 4th, 5th, 6th or 7th carbon position of the aldonic acid. When one carbohydrate monomer is attached to the aldonic acid, the resulting compound may be called alloheptobionic acid, altroheptobionic acid, glucoheptobionic acid, mannoheptobionic acid, guloheptobionic acid, idoheptobionic acid, galactoheptobionic acid or taloheptobionic acid.
A common carbohydrate monomer such as glucose contains an aldehyde group (first carbon position) and five hydroxyl groups, whereas fructose contains a keto group (at second carbon position) and five hydroxyl groups. Many carbohydrate monomers form a five (furanoside) or six (pyranoside) member ring between the aldehyde or keto group and one of the hydroxyl groups at 4th or 5th carbon position of the molecule. A newly formed hydroxyl group (anomeric hydroxyl) at the original functional group has two isomers: alpha or beta anomer, depending on down or up of the hydroxyl position. A disaccharide is usually formed from two monosaccharides (carbohydrate monomers) by eliminating one mole of water between two anomeric hydroxyl groups (non-reducing disaccharide) or between one anomeric hydroxyl of the second monomer and one of the hydroxyl in the first monomer (reducing disaccharide). A non-reducing disaccharide such as sucrose formed from fructose and glucose can not be oxidized to an aldonic acid, whereas a reducing disaccharide such as maltose formed from two glucose molecules can be oxidized to maltobionic acid. Oligosaccharides containing three to ten monomers may be formed in the same manner as in that of disaccharides. As an alternative example, tetrasaccharides may also be formed from two disaccharides.
Since the chemical link between two carbohydrate monomers can be at different carbon positions, numerous different oligosaccharides may be formed. The same is true for oligosaccharide aldonic acids. For example, the disaccharides maltose and cellobiose are both formed from two glucose molecules linked between the anomeric hydroxyl of the second glucose and the hydroxyl at the 4th carbon position of the first glucose molecule. The only difference is that maltose is an alpha anomer and cellobiose is a beta anomer. The same is true when these two disaccharides are oxidized to aldonic acids. The only difference between maltobionic acid and cellobionic acid is that the former is an alpha and the latter is a beta anomer.
Many disaccharides which may be converted to bionic acids include glycerbioses, erythrobioses, threobioses, ribobioses, arabinobioses, xylobioses, lyxobioses, allobioses, altrobioses, glucobioses, mannobioses, gulobioses, idobioses, galactobioses, talobioses, alloheptobioses, altroheptobioses, glucoheptobioses, mannoheptobioses, guloheptobioses, idoheptobioses, galactoheptobioses, taloheptobioses, maltose, isomaltose, lactose, cellobiose, gentiobiose, laminaribiose, kojibiose, melibiose, nigerose, rutinose and sophorose. Bionic acids may be obtained from these disaccharides by an oxidation process with hypoiodite, bromine water or enzyme.
In accordance with the present invention, the generic structure of oligosaccharide aldonic acids may be represented as follows:
R1(CHOR2)m(CH2)nCOOR3
wherein:
R1 and R3 are independently H or an alkyl, aralkyl or aryl group of saturated or unsaturated, straight or branched chain or cyclic form, having 1 to 25 carbon atoms;
m is 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
R2 is independently selected from H or any carbohydrate having from 1 to 9 monomers in each (CHOR2), and at least one R2 is a carbohydrate. For example, when m=5, one of the five R2 may be a carbohydrate and the remaining four R2 may be H;
H attached to carbon atom may be substituted by I, F, Cl, Br, NH2, NHCOCH3, SH, or alyl, alkoxyl, aralkyl or aryl group of saturated or unsaturated, straight or branched chain or cyclic form, having from 1 to 9 carbon atoms;
R1, R2, OR2 or H may carry or be substituted with CHO, COOH, sulfate, phosphate, nitrate, or lower alkoxyl having from 1 to 5 carbon atoms;
H of the OH group may be substituted by an acyl group having from 2 to 25 carbon atoms, such as acetyl (CH3CO), propanoyl (CH3CH2CO), octanoyl [CH3(CH2)6CO], octadecanoyl [CH3(CH2)16CO], eicosanoyl [CH3(CH2)18CO], tetraeicosanoyl [CH3(CH2)22CO] or benzoyl (C6H5CO) group.
Oligosaccharide aldonic acids according to the present invention may be present as isomeric D, L, DL or any other isomeric or non-isomeric form, saturated or unsaturated, straight or branched chain or cyclic form, free acid, ester, lactone, salt or partial salt form with organic or inorganic alkali.
The preferred oligosaccharide aldonic acids contain 2 to 6 carbohydrate monomers, and more preferred ones contain 2 to 3 carbohydrate monomers, and the most preferred oligosaccharide aldonic acids contain two carbohydrate monomers. The most preferred oligosaccharide aldonic acids may be called bionic acids which contain two carbohydrate monomers. In the bionic acid, the chemical link between the two carbohydrate monomers can be at any carbon position. The preferred link is between the anomeric carbon of the second monomer chemically bond to any position other than the first carbon position of the first monomer. In addition, two anomeric isomers such as alpha and beta isomers can be formed when the second monomer is linked to the first monomer, and therefore numerous different bionic acids may exist. For example, glucobionic acids include maltobionic acid and cellobionic acid.
As an example, chemical structures of some oligosaccharaide aldonic acids are depicted below: 
Oligosaccharide aldonic acid lactones are usually obtained from their aldonic acids by eliminating one mole of water through intramolecular cyclization between the carboxyl group and one of the hydroxyl groups. Common lactones consist of five or six member rings.
Examples of lactone form include lactobionolactone, maltobionolactone, isomaltobionolactone, cellobionolactone, chitobionolactone, gentiobionolactone, glucobionolactone, galactobionolactone, mannobionolactone, ribobionolactone, kojibionolactone, xylobionolactone, arabinobionolactone, nigerobionolactone, laminarabinobionolactone, maltotrionolactone, isomaltotrionolactone, chitotrionolactone, cellotrionolactone, gentiotrionolactone, maltotetraonolactone, cellotetraonolactone and chitotetraonolactone.
Examples of ester form include methyl lactobionate, ethyl lactobionate, propyl lactobionate, benzyl lactobionate, methyl maltobionate, ethyl maltobionate, propyl maltobionate, benzyl maltobionate, methyl cellobionate, ethyl cellobionate, propyl cellobionate and benzyl cellobionate.
Examples of acyl form include acetyl lactobionic acid, acetyl maltobionic acid and acetyl cellobionic acid.
Examples of both acyl and ester form include acetyl lactobionic acid methyl, ethyl or propyl ester; acetyl maltobionic acid methyl, ethyl or propyl ester; acetyl cellobionic acid methyl, ethyl or propyl ester.
On one embodiment of the inventions, the group of oligosaccharide aldonic acids and related compounds according to the invention are the group of compounds discussed herein, but excluding lactobionic acid. In another embodiment of the invention the group of oligosaccharide aldonic acids and related compounds according to the invention are the group of compounds discussed herein, but excluding lactobionic acid and salts, lactones, and thereof.
Oligosaccharide aldonic acids may be classified into groups according the number of carbohydrate monomers such as aldobionic acid, aldotrionic acid, aldotetraonic acid, aldopentaonic acid, aldohexaonic acid, aldoheptaonic acid, aldooctaonic acid, aldononaonic acid and aldodecaonic acid. The preferred groups are aldobionic acid up to aldohexaonic acid, with more preferred groups of aldobionic acid up to aldotetraonic acid, and with most preferred groups being aldobionic acid and aldotrionic acid.
Many different aldobionic acids and aldotrionic acids exist due to various carbohydrate monomers and different linking positions between two monomers. For example, even in the smallest molecule of glycerbionic acid (six carbon atoms) formed from glyceraldehyde (second monomer) and glyceric acid, there are two different glycerbionic acids; linking at 2nd or 3rd carbon position of the glyceric acid. Glycerbionic acids also include various second monomers linked to glyceric acid at the 2nd or 3rd carbon position. The second monomers include erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, talose, 6-deoxymannose, 2-deoxyaminoglucose and fucose. Some representative oligosaccharide aldonic acids include the following:
(i) Aldobionic Acids (Bionic Acids)
These bionic acids consist of one carbohydrate monomer linked to an aldonic acid, and include glycerbionic acids, erythrobionic acids, threobionic acids, ribobionic acids, arabinobionic acids, xylobionic acids, lyxobionic acids, allobionic acids, altrobionic acids, glucobionic acids, mannobionic acids, gulobionic acids, idobionic acids, galactobionic acids, talobionic acids, alloheptobionic acids, altroheptobionic acids, glucoheptobionic acids, mannoheptobionic acids, guloheptobionic acids, idoheptobionic acids, galactoheptobionic acids, taloheptobionic acids, chitobionic acids, hyalobiouronic acids, hyalourobionic acids, chondrosines, chondrosinbionic acids, cellobiouronic acids, and cellourobionic acids.
As an example, glucobionic acids include lactobionic acid, isolactobionic acid, maltobionic acid, isomaltobionic acid, cellobionic acid, gentiobionic acid and laminarabionic acid. All these bionic acids are formed from the same or a different carbohydrate monomer linked to gluconic acid through a different or the same position. Other individually named bionic acids include melibionic acid, nigerobionic acid, rutinobionic acid, sophorobionic acid and kojibionic acid.
(ii) Aldotrionic Acids (Trionic Acids)
These trionic acids consist of two carbohydrate monomers linked jointly or separately to an aldonic acid, and include glycertrionic acids, erythrotrionic acids, threotrionic acids, ribotrionic acids, arabinotrionic acids, xylotrionic acids, lyxotrionic acids, allotrionic acids, altrotrionic acids, glucotrionic acids, mannotrionic acids, gulotrionic acids, idotrionic acids, galactotrionic acids, talotrionic acids, alloheptotrionic acids, altroheptotrionic acids, glucoheptotrionic acids, mannoheptotrionic acids, guloheptotrionic acids, idoheptotrionic acids, galactoheptotrionic acids, taloheptotrionic acids, chitotrionic acids, hyalotriouronic acids, hyalourotrionic acids, chondrosintrionic acids, cellotriouronic acids and cellourotrionic acids.
(iii) Other Oligosaccharide Aldonic Acids and Related Compounds
Aldonic acids with higher molecular weight may consist of three to nine carbohydrate monomers linked jointly or separately to an aldonic acid, and include aldotetraonic acids, aldopentaonic acids, aldohexaonic acids, aldoheptaonic acids, aldooctaonic acids, aldononaonic acids and aldodecaonic acids. Miscellaneous or related aldonic acids include those which are not readily represented or included in the above generic structure, or which have additional functional groups in the molecules, such as a carbohydrate linked to an uronic acid, which may or may not be represented by the above generic structure. A sulfate, phosphate, nitrate group, amino, acetamino group etc. may be substituted at H or OH similar to that of chitin, chitosan, hyaluronic acid, chodroitin sulfate, heparin, etc. to form substituted oligosaccharide aldonic acids.
2. Topical Uses of Oligosaccharide Aldonic Acids and Related Compounds
(i) Oligosaccharide Aldonic Acids and Related Compounds
Compositions comprising an oligosaccharide aldonic acid or related compound described herein have numerous beneficial effects and a broad range of uses. These compositions can comprise one or more than one oligosaccharide aldonic acid or related compound.
According to one aspect of the invention, these compositions may be used for general care; moisturizing; dry skin; reducing irritation or inflammation of or soothing skin and mucosa or treatment or prevention of skin or mucosa irritation or inflammation caused by external factors, such as chemicals; skin smoothing and itchy skin; as well as for treatment and prevention, of various cosmetic conditions and dermatological disorders, including those associated with intrinsic and/or extrinsic aging, as well as with changes or damage caused by extrinsic factors. In a preferred embodiment, the compositions may be used for skin, hair and nail changes associated with intrinsic and/or extrinsic aging, and changes or damage caused by extrinsic factors such as sunlight, radiations, air pollution, wind, cold, dampness, heat, chemicals, smoke, and cigarette smoking. In addition, the compositions of the present invention may be used to treat skin wounds, for example in aiding the healing of skin cuts, tears, lacerations, burns, punctures, and other wounds.
According to another aspect of the invention, these compositions may be used for general care, as well as treatment and prevention of diseases and conditions, of the oral, nasal and vaginal mucosa. For example, the compositions may be used for care and treatment of blemished, unhealthy, damaged, irritated, or abnormal oral, nasal or vaginal mucosa, and gum diseases.
According to still another aspect of the invention, these composition may be used for general oral care, as well as treatment and prevention of oral and gum diseases.
With respect to age associated skin changes, the underlying bases of these changes is described in U.S. Pat. No. 4,603,146 (Kligman). In particular, the underlying causes of skin changes associated with aging can be more easily understood in view of the following summary of the changes in the epidermis and dermis as aging progresses.
With increasing age and exposure of human to sun and other environmental traumas, cells divide at a slower rate (decreased capacity to renew themselves). They show marked irregularities in size, shape and staining properties; orderliness (polarity) from below to above is lost. The thickness of the epidermis decreases (atrophy). The horny layer which comprises the barrier against water loss and penetration of chemicals becomes abnormal due to the shedding (exfoliation) of cells in large group or clusters instead of as individual cells, resulting in roughness, scaling and dryness. There is loss of the orderly transformation of living epithelial cells into cornified dead cells which are shed at the surface, that is, differentiation is impaired. Aberrant differentiation results in numerous foci of abnormal epithelial growths or tumors, the most frequent and important of which are actinic keratoses. After many years these can transform into frank skin cancers called basal cell and squamous cell cancers. Pigment producing cells (melanocytes) can also become altered forming flat, dark growths (lentigo melanoma) which may progress to malignant melanoms.
The cells which make the fibers of the dermis become smaller and sparser with increasing age, usually in sun-damaged facial skin. There is a great loss of collagen fibers resulting in looseness and easy stretchability of the skin; elastic fibers become abnormal so that the skin does not promptly snap back after being stretched. Since the fibrous components comprise more than 90% of the bulk of skin of which 95% is collagen, the degradation of these fibers, especially collagen, is mainly responsible for wrinkling, laxness and loss of elasticity.
Additionally, small blood vessels become thin walled, dilated and often ruptured. Vascular supply thereby becomes compromised.
The signs of nail and hair changes associated with intrinsic aging and the damages caused by extrinsic factors include thinning of hair and nail plate; lack of lubricants and luster, and uneven surface of hair and nails; fragility and splitting of hair and nails; and reduction of flexibility, resiliency, and elasticity of hair and nails.
The conventional management of signs of aging skin has been the use of cosmetics, as well as medical procedures such as phenol, trichloroacetic acid, and other chemical peels, and plastic surgery, etc. Such medical procedures are costly and risky with serious side effects, and the treatments alter only the cosmetic appearance of the skin, without any significant modifications of the underlying aging process.
Topical application to the skin, hair or nails of a composition of the present invention is beneficial for various cosmetic conditions and dermatological disorders including those associated with intrinsic and/or extrinsic aging and extrinsic factors, and also including those characterized by the foregoing changes to the skin, hair and nails. Exemplary indications are characterized as disturbed keratinization, defective syntheses of dermal components, and changes associated with aging of skin, nail and hair; and those indications which include dryness or loose of skin, nail and hair; xerosis; ichthyosis; palmar and plantar hyperkeratoses; uneven and rough surface of skin, nail and hair; dandruff; Darier""s disease; lichen simplex chronicus; keratoses; acne; pseudofolliculitis barbae; irritation; dermatoses; eczema; psoriasis; itchy scalp and skin; pruritus; warts; herpes; age spots; lentigines; melasmas; blemished skin; mottled skin; hyperkeratoses; hyperpigmented skin; abnormal or diminished syntheses of collagen, glycosaminoglycans, proteoglycans and elastin as well as diminished levels of such components in the dermis; stretch marks; skin lines; fine lines; wrinkles; thinning of skin, nail plate and hair; skin thickening due to elastosis of photoaging, loss or reduction of skin, nail and hair resiliency, elasticity and recoilability; lack of skin, nail and hair lubricants and luster; dull and older-looking skin, nail and hair; fragility and splitting of nail and hair; and other topical conditions and indications.
(ii) Combination Compositions
In addition, compositions comprising one or more than one oligosaccharide aldonic acid or related compound may also be incorporated into a composition comprising a cosmetic, pharmaceutical or other topical agent to enhance or create synergetic effects.
In accordance with this aspect of the invention, the compositions of the present invention may contain one or more oligosaccharide aldonic acids or related compounds to magnify the therapeutic effect of an unrelated cosmetic or pharmaceutical agent. At least one compound selected from the group consisting of oligosaccaride aldonic acids and related compounds may be incorporated into composition containing a cosmetic or pharmaceutical agent for any of the uses described above. It has been found that such incorporation results in magnified therapeutic efficacies which are not simply additive effects.
Most pharmaceutical drugs produce their therapeutic effects by first interacting with their receptors in the target tissues. Many drug receptors are functional macromolecules such as enzymes, cell membrane components or certain components of cells. The binding affinity or interacting property of a drug toward its specific receptor molecule is intimately governed by the chemical structure of the drug. Since most pharmaceutical agents are chemically different from oligosaccaride aldonic acids and related compounds of the instant invention, the respective receptor molecule should be different and so are the pharmacological actions and the therapeutic effects. Under such conditions if an oligosaccharide aldonic acid and/or related compound is incorporated into a composition containing a pharmaceutical agent, one of the following two consequences may arise:
(a) No enhancement or any substantial changes in either effect. In this case, the overall clinical effect would be a mixed effect, i.e. the effect due to the pharmaceutical agent alone mixed with the effect due to the oligosaccharide aldonic acid and/or related compound alone. Also in this case, the interaction between the pharmaceutical agent and its receptor molecule is not affected nor interfered by the presence of oligosaccharide aldonic acid and/or related compound. Nor does the oligosaccharide aldonic acid and/or related compound assist in or enhance the binding affinity or the interaction of the pharmaceutical agent toward its receptor molecule. The clinical results from such combination composition would be just the mixed effects.
(b) Amplified therapeutic action or substantial loss of therapeutic action in either effect. In this case, the interaction between the pharmaceutical agent and its receptor molecule is affected either positively or negatively by the presence of an oligosaccharide aldonic acid and/or related compound. From the point of positive effect, the oligosaccharide aldonic acid and/or related compound may produce an amplified effect by either increasing the affinity of the receptor molecule toward the pharmaceutical agent, acting as a better and more efficient coenzyme or as an activator by disrupting barriers and removing obstacles for better binding of the agent toward its receptor molecule; for example, enzyme activation by removal of natural inhibitors. In all these cases the overall clinical results would be due to magnified therapeutic effects which are not predictable from either effect alone.
From the point of negative effect, an oligosaccharide aldonic acid or related compound might interfere with or decrease the binding affinity of the pharmaceutical agent toward its receptor molecule; i.e., acting as an competitor or inhibitor. In such case, the overall clinical results should be due to substantial diminishment or completely loss of therapeutic effects, which is also unpredictable from either effect alone.
At present we do not know the exact mechanism involved in the synergistic effect or unexpected increase in therapeutic effect of a cosmetic or dermatological agent by an oligosaccharide aldonic acid. The following are relevant observations.
(1) Not Due to Enhanced Penetration
The enhanced and substantial increase in therapeutic effects of a cosmetic or dermatological agent incorporated with an oligosaccharide aldonic acid is not simply due to an increased penetration of the topical agent into the skin, nor due to a simple addition or combination effects.
(2) Re-activation from Therapeutic Non-responsiveness
Tachyphylaxis or so-called xe2x80x9cdrug resistancexe2x80x9d is frequently encountered with corticosteroid or other drug therapy for topical treatment of psoriasis, eczema etc. On continued topical use, many patients develop tachyphylaxis to corticosteroids, and the lesions very often do not respond any more to topically applied corticosteroid compositions, even under occlusive dressings to enhance penetration. The exact nature of such resistance to the drug is not known. One of the proposed hypotheses is that the available level of receptor molecule(s) for corticosteroids in the skin is diminished or exhausted completely due to continued daily use of the drugs. However, it is not known whether the receptor level is really low or the active site of the receptor molecule is covered-up by an inhibitor.
When tachyphylaxis is encountered from corticosteroid alone therapy, incorporation of an oligosaccharide aldonic acid into the corticosteroid composition would eradicate the drug resistance. If desired, the composition containing an oligosaccharide aldonic acid alone may be applied alternatively with the corticosteroid therapy.
(3) Eradication of Rebound Worsening
One well-known side effect associated with continued use of certain drugs, such as corticosteroids, is a rebound worsening of the disease if the treatment is discontinued. The mechanism of worsening is not known. It has been speculated that the antiinflammatory property of corticosteroids is to suppress the immunological expression of the disease. The disease process is not eradicated nor substantially modified, but is only held-up like river water is held-up by a dam. Discontinuation of the therapy is like removing the dam.
To prevent rebound worsening encountered with corticosteroids is to incorporate an oligosaccharide aldonic acid into the composition containing a corticosteroid, or to use the oligosaccharide aldonic acid alternately with the corticosteroid.
(4) Prevention or Eradication of Side-effects
Other well-known side effects associated with continued topical use of a corticosteroid are thinning and atrophy of the skin. To prevent or eliminate such side effects, an oligosaccharide aldonic acid may be incorporated into the composition containing a corticosteroid, or may be used alternately with the corticosteroid.
We have found that, in most cases, therapeutic effects of cosmetic and pharmaceutical agents are amplified when an oligosaccharide aldonic acid or related compound is incorporated into the composition, i.e., consequence (b) above is observed.
The cosmetic and pharmaceutical agents which may be actuated by oligosaccharide aldonic acids and related compounds include those that improve or eradicate age spots, keratoses and wrinkles; local analgesics and anesthetics; antiacne agents; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antidandruff agents; antidermatitis agents; antihistamine agents; antipruritic agents; antiemetics; antimotionsickness agents; antiinflammatory agents; antihyperkeratolytic agents; antiperspirants; antipsoriatic agents; antiseborrheic agents; hair conditioners and hair treatment agents; antiaging and antiwrinkle agents; sunblock and sunscreen agents; skin lightening agents; depigmenting agents; vitamins; corticosteroids; tanning agents; humectants; hormones; retinoids; gum disease or oral care agents; topical cardiovascular agents; corn, callus and wart removing agents; dipilating agents; and other dermatologicals.
Some examples of cosmetic and pharmaceutical agents are aclovate, acyclovir, acetylsalicylic acid, adapalene, albuterol, aluminum acetate, aluminum chloride, aluminum hydroxide, aluminum chlorohydroxide, amantadine, aminacrine, aminobenzoic acid (PABA), aminocaproic acid, aminosalicylic acid, amitriptyline, anthralin, ascorbic acid, ascoryl palimate, atropine, azelaic acid, bacitracin, bemegride, beclomethasone dipropionate, benzophenone, benzoyl peroxide, betamethasone dipropionate, betamethasone valerate, brompheniramine, bupivacaine, butoconazole, calcipotriene, camphor, capsaicin, carbamide peroxide, chitosan, chlorhexidine, chloroxylenol, chlorpheniramine, ciclopirox, clemastine, clindamycin, clioquinol, clobetasol propionate, clotrimazole, coal tar, cromolyn, crotamiton, cycloserine, dehydroepiandrosterone, desoximetasone, dexarnethasone, diphenhydramine, doxypin, doxylamine, dyclonine, econazole, erythromycin, estradiol, ethinyl estradiol, fluocinonide, fluocinolone acetonide, 5-fluorouracil, griseofulvin, guaifenesin, haloprogin, hexylresorcinol, homosalate, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrogen peroxide, hydroquinone, hydroquinone monoether, hydroxyzine, ibuprofen, ichthanmol, imiquimod, indomethacin, ketoconazole, ketoprofen, kojic acid, lidocaine, meclizine, meclocycline, menthol, mepivacaine, methyl nicotinate, methyl salicylate, metronidazole, miconazole, minocycline, minoxidil, monobenzone, mupirocin, naftifine, naproxen, neomycin, nystatin, octyl methoxycinnamate, octyl salicylate, oxybenzone, oxiconazole, oxymetazoline, padimate O, permethrin, pheniramine, phenol, phenylephrine, phenylpropanolamine, piperonyl butoxide, podophyllin, podofilox, povidone iodine, pramoxine, prilocaine, procaine, promethazine propionate, propranolol, pseudoephedrine, pyrethrin, pyrilamine, resorcinol, retinal, 13-cis retinoic acid, retinoic acid, retinol, retinyl acetate, retinyl palmitate, salicylamide, salicylic acid, selenium sulfide, shale tar, sulconazole, sulfur, sulfadiazine, tazarotene, terbinafine, terconazole, tetracaine, tetracycline, tetrahydrozoline, thymol, tioconazole, tolnaftate, triamcinolone diacetate, triamcinolone acetonide, triamcinolone hexacetonide, triclosan, triprolidine, undecylenic acid, urea, vitamin E acetate, wood tar, and zinc pyrithione,
Another example of cosmetic or other agents that may be combined with one or more oligosaccharide aldonic acids and related compounds include hydroxyacids, ketoacids and related compounds. Examples of hydroxy acids include hydroxymonocarboxylic acids, hydroxydicarboxylic acids, 2-hydroxycarboxylic acids, other hydroxycarboxylic acids, 2-ketocarboxylic acids and related compounds. See, for example, U.S. Pat. Nos. 5,422,370, 5,547,988, 5,470,880, and 5,385,938. The hydroxy acids may exist as a free acid, an ester, a lactone, in salt form with an organic base or an inorganic alkali, and as stereoisomers. Representative examples of hydroxy acids and related compounds include glycolic acid, mandelic acid, lactic acid, tropic acid, methyllactic acid, tartaric acid, citric acid, glucuronic acid, ribonic acid, gluconolactone, ribonolactone, gycolyl glycollate, lactyl lactate, trilactic acid and polylactic acid.
Yet another example of cosmetic or other agents that may be combined with one or more oligosaccharide aldonic acids or related compounds include phenyl alpha acyloxyalkanoic acids and derivatives thereof. These compounds may exist in a free acid, or salt form, or as stereoisomers. See, for example, U.S. Pat. Nos. 5,258,391 and 5,643,949. Representative example of such compounds include diphenyl alpha acetoxyacetic acid, phenyl alpha acetoxyacetic acid, phenyl alpha methyl alpha acetoxyacetic acid, phenyl alpha acetoxypropanoic acid, and 2-phenyl beta acetoxypropanoic acid.
Still another example of cosmetic or other agents that may be combined with one or more oligosaccharide aldonic acids or related compounds include N-acetyl-aldosamines, N-acetylamino acids and related N-acetyl compounds. These compounds may exist in a free acid, lactone or salt form, or as stereoisomers. See, for example, U.S. patent application Ser. No. 09/227,213, filed Jan. 8, 1999. Representative example of such compounds include N-acetyl-glucosamine and N-acetyl-proline.
When the compositions according to the present invention are used for general care, moisturizing, dry skin, skin smoothing and itchy skin, as well as for treatment and prevention, of various cosmetic conditions and dermatological disorders, including those associated with intrinsic and/or extrinsic aging, as well as with changes or damage caused by extrinsic factors, examples of suitable cosmetic or other agents that may be combined with one or more oligosaccharide aldonic acids or related compounds include: hydroxyacids, ketoacids and related compounds; phienyl alpha acyloxyalkanoic acids and derivatives thereof N-acetyl-aldosamines, N-acetylamino acids and related N-acetyl compounds; those that improve or eradicate age spots, keratoses and wrinkles; local analgesics and anesthetics; antiacne agents; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antidandruff agents; antidermatitis agents; antihistamine agents; antipruritic agents; antiemetics; antimotionsickness agents; antiinflammatory agents; antihyperkeratolytic agents; antiperspirants; antipsoriatic agents; antiseborrheic agents; astringents; cleansing agents; hair conditioners and hair treatment agents; antiaging and antiwrinkle agents; sunblock and sunscreen agents; skin lightening agents; depigmenting agents; vitamins; corticosteroids; tanning agents; hormones; retinoids; topical cardiovascular agents; corn, callus and wart removing agents; and other dermatologicals.
Some examples of cosmetic and pharmaceutical agents are aclovate, acyclovir, acetylsalicylic acid, adapalene, albuterol, aluminum acetate, aluminum chloride, aluminum hydroxide, aluminum chlorohydroxide, amantadine, aminacrine, aminobenzoic acid (PABA), aminocaproic acid, arninosalicylic acid, amitriptyline, anthralin, ascorbic acid, ascoryl palimate, atropine, azelaic acid, bacitracin, bemegride, beclomethasone dipropionate, benzophenone, benzoyl peroxide, betamethasone dipropionate, betamethasone valerate, brompheniramine, bupivacaine, butoconazole, calcipotriene, camphor, capsaicin, carbamide peroxide, chitosan, chlorhexidine, chloroxylenol, chlorpheniramine, ciclopirox, clemastine, clindamycin, clioquinol, clobetasol propionate, clotrimazole, coal tar, cromolyn, crotamiton, cycloserine, dehydroepiandrosterone, desoximetasone, dexamethasone, diphenhydramine, doxypin, doxylamine, dyclonine, econazole, erythromycin, estradiol, ethinyl estradiol, fluocinonide, fluocinolone acetonide, 5-fluorouracil, griseofulvin, guaifenesin, haloprogin, hexylresorcinol, homosalate, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrogen peroxide, hydroquinone, hydroquinone monoether, hydroxyzine, ibuprofen, ichtharnmol, imiquimod, indomethacin, ketoconazole, ketoprofen, kojic acid, lidocaine, meclizine, meclocycline, menthol, mepivacaine, methyl nicotinate, methyl salicylate, metronidazole, miconazole, ninocycline, minoxidil, monobenzone, mupirocin, naftifine, naproxen, neomycin, nystatin, octyl methoxycinnamate, octyl salicylate, oxybenzone, oxiconazole, oxymetazoline, padimate O, permethrin, pheniramine, phenol, phenylephrine, phenylpropanolamine, piperonyl butoxide, podophyllin, podofilox, povidone iodine, pramoxine, prilocaine, procaine, promethazine propionate, propranolol, pseudoephedrine, pyrethrin, pyrilamine, resorcinol, retinal, 13-cis retinoic acid, retinoic acid, retinol, retinyl acetate, retinyl palmitate, salicylamide, salicylic acid, selenium sulfide, shale tar, sulconazole, sulfur, sulfadiazine, tazarotene, terbinafine, terconazole, tetracaine, tetracycline, tetrahydrozoline, thymol, tioconazole, tolnaftate, triamcinolone diacetate, triamcinolone acetonide, triamcinolone hexacetonide, triclosan, triprolidine, undecylenic acid, urea, vitamin E acetate, wood tar, and zinc pyrithione. Other examples of suitable cosmetic and pharmaceutical agents are well known to those of skill in the art.
When the compositions according to the present invention are used for general care, as well as treatment and prevention of diseases and conditions, of the oral and vaginal mucosa, examples of suitable cosmetic or other agents that may be combined with one or more oligosaccharide aldonic acids or related compounds include: hydroxyacids, ketoacids and related compounds; phenyl alpha acyloxyalkanoic acids and derivatives thereof N-acetyl-aldosamines, N-acetylamino acids and related N-acetyl compounds; local analgesics and anesthetics; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antihistamine agents; antipruritic agents; antiemetics; antimotion sickness agents; antiinflammatory agents; vitamins; corticosteroids; hormones; and gum disease or oral care agents.
Some examples of cosmetic and pharmaceutical agents are clotrimazole, ketoconazole, miconazole, griseofulvin, econazole, metronidazole, hydroxyzine, diphenhydramine, pramoxine, lidocaine, procaine, mepivacaine, monobenzone, anthralin, coal tar, benzocaine, benzoyl peroxide, erythromycin, tetracycline, clindamycin, meclocycline, hydroquinone, hydroquinone monoether, minocycine, naproxen, ibuprofen, theophylline, cromolyn, albuterol, retinol, retinyl acetate, retinyl palmitate, retinal, retinoic acid, 13-cis retinoic acid, hydrocortisone, hydrocortisone 21-acetate, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, betamethasone valerate, betamethasone dipropionate, triamcinolone acetonide, fluocinonide, clobetasol, propionate, benzoyl peroxide, kojic acid, crotamiton, propranolol, promethazine, salicylic acid, vitamin E and vitamin E acetate. Other examples of suitable cosmetic and pharmaceutical agents are well known to those of skill in the art.
When the compositions according to the present invention are used for general oral care, as well as treatment and prevention of oral and gum diseases, examples of suitable cosmetic or other agents that may be combined with one or more oligosaccharide aldonic acids or related compounds include: hydroxyacids, ketoacids and related compounds; phenyl alpha acyloxyalkanoic acids and derivatives thereof N-acetyl-aldosamines, N-acetylamino acids and related N-acetyl compounds; analgesics and anesthetics; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antiinflammatory agents; vitamins; and other gum disease or oral care agents.
Some examples of cosmetic and pharmaceutical agents are triclosan, sodium flouride, zinc chloride, zinc citrate, zinc sulfate, chlorhexidine, chlorhexidine and digluconate.
When the compositions according to the present invention are used for treating skin wounds, for example in aiding the healing of skin cuts, tears, lacerations, burns, punctures, and other wounds, examples of suitable cosmetic or other agents that may be combined with one or more oligosaccharide aldonic acids or related compounds include: hydroxyacids, ketoacids and related compounds; phenyl alpha acyloxyalkanoic acids and derivatives thereof N-acetyl-aldosaniines, N-acetylamino acids and related N-acetyl compounds; analgesics and anesthetics; wound cleansers; antibacterials; antiyeast agents; antifungal agents; antiviral agents; antiinflammatory agents; skin lightening agents; depigmenting agents; vitamins; burn relief agents; and corticosteroids.
(iii) Molecular Complex and Slow-release Compositions
A formulation containing an oligosaccharide aldonic acid usually has a pH of below 3.0, and the composition may irritate human skin of atopic or sensitive skin type on repeated topical application, due to lower pH or uncontrolled release and penetration of the acid into stratum corneum of the skin. We have found that an oligosaccharide aldonic acid can form a buffer system with an alkali and/or a molecular complex with a complexing agent, and the resulting composition has the following attributes: (1) easy and simple process in formulating, (2) raising the overall pH of the formulation to above 3.0, (3) having a buffer system in the composition, (4) no irritation or minimal stinging to sensitive skin, (5) controlled or slow-release of the active ingredient into the skin, and (6) retaining the therapeutic efficacy. The substance used for neutralizing, partially neutralizing, salt forming, buffering or complexing may be an inorganic or organic alkali, or amphoteric.
An alkali is defined as a substance which shows a pH of above 7.0 in a solution. Common inorganic alkalis include for example ammonium hydroxide, ammonium phosphate, ammonium carbonate or bicarbonate, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate, and the like alkalis formed from potassium, calcium, magnesium, strontium, aluminum, zinc, and lithium. Common organic alkalis are amines, hydroxylamines, imines, guanidines, amine oxides, alkanolamines, alkoxylated amines and alkylamido alkylamines, such as diethanolamine, triethanolamine, isopropanolamine, diisopropanolamine, triisopropanolamine, aminobutanol, aminoethyl propanediol, aminomethyl propanol, aminomethyl propanediol, isopropylamine, methylethanolamine, diisopropylamine, dipropylenetriamine, glucamine, N-methylglucamine, morpholine, tromethamine, cocamines, soyamines, oleamines, stearamines, quaterniums and the like. The buffer system in the composition consists of two species; namely oligosaccharide aldonic free acid and oligosaccharide aldonate anion despite an inorganic or organic alkali.
A molecular complexing agent with an oligosaccharide aldonic acid may be an amphoteric or non-amphoteric substance. The mole ratio of a complexing agent may be higher than one, however the preferred ratio is less than one, and most preferred ratio is from 0.1 to 0.5. The amphoteric substance by definition should have both an acidic and a basic functional groups in the molecule, and can behave both as an acid and an alkali in a solution. Inorganic amphoteric substances include certain metallic oxides such as aluminum oxide and zinc oxide. However, the preferred amphoteric system consists of an organic amphoteric substance. The molecule of an organic amphoteric substance should consist of at least one acidic function selected from carboxylic, phosphoric and sulfonic groups, and at least one basic function from amino, imino and guanido groups. Examples of organic amphoteric substances include amino acids, peptides, polypeptides, proteins and related compounds such as glycine, arginine, lysine, cysteine, proline, glutamine, tryptophan, asparagine, tyrosine, ornithine, citrulline, creatine, histidine and canavanine.
In an amphoteric system, the molecular complex consists of several ionic species. For example, a triple ionic complex will be formed from one mole of an oligosaccharide aldonic acid (having one reactive group) with one mole of glycine (having two functional groups), and a quadruple ionic complex will be formed with arginine or lysine (having three functional groups). Due to ionic bonds and forces between the positive charge and the negative charge of the molecular complex ions, the release and penetration of the oligosaccharide aldonic acid into the skin will be controlled at moderate and optimal rate. Thus the slow-release system can reduce or eliminate skin irritation without compromising the intended therapeutic effects.
The non-amphoteric complexing agents are organic alkalis which include organic amines, polyamines, hydroxylamines, imines, guanidines, amine oxides, alkanolamines, alkoxylated amines, alkylamido alkylamines, amino acid esters, amino acid amides, aminosaccharides, aminoalditols, aminocyclitols, fattyamines, imidazolines and the like which are capable of forming the molecular complex and/or salts with oligosaccharide aldonic acids. The molecular weight of a complexing agent may range from 50 to 10,000, however the preferred one ranges from 100 to 600. Examples of some complexing agents include creatinine, glycine ethyl ester, arginine ethyl ester, lysine methyl ester, proline ethyl ester, citrulline benzyl ester, glycinamide, argininamide, prolinamide, lysinamide, glucamine, methylglucamine, glucosamines and glucosylamines, other glycosamines and glycosylamines, aminoinositols, chitosan, stearamidoethyl diethylamine, stearamidopropyl dimethylamine, stearamidoethyl diethanolamine, quaternary ammonium hydroxide.
(iv) Antioxidant Properties
An antioxidant may be defined as a substance capable of preventing or inhibiting oxidation. Most oligosaccharide aldonic acids are antioxidant compounds because they possess two or more hydroxyl groups near the carboxylic group. The antioxidant property is readily determined by using any one of the following test methods: prevention or retardation of air oxidation of (a) anthralin, (b) hydroquinone, or (c) banana peel. A freshly prepared anthralin solution or cream is bright yellow, and an air oxidized one is brownish or black. A hydroquinone solution or cream is colorless or white color, and an air oxidized one is brownish or black. A freshly peeled banana peel is light yellow in color and an oxidized one ranges in color from tan, dark tan, brown to brownish black.
For example, in control experiments, fresh banana peels cut into sizes of 1xc3x972 cm in 50 mm plastic petri dishes containing 5 ml water at neutral or acidic pH changed in color from white-yellowish to tan within 6 hours at room temperature, and changed to dark tan color during the next period of 24 to 72 hours. When fresh banana peels were placed in dishes containing 5 ml of 0.1 M lactobionic acid under the same conditions, the banana peels remained white-yellowish for the period of 24 hours, and changed in color to tan after 72 hours. The above test results show that lactobionic acid is an antioxidant substance. Using anthralin and hydroquinone test methods also confirmed that lactobionic acid is a moderate antioxidant.
(v) Gel Matrix Formation
In contrast to an alpha hydroxyacid and polyhydroxyacid, an oligosaccharide aldonic acid can form a gel matrix when its aqueous solution is evaporated at room temperature. The transparent gel obtained retains certain amount of water forming a clear gel matrix. The amount of water retention depends on individual oligosaccharide aldonic acid. Examples of gel matrix preparations are provided below.
The formation of a gel matrix between an oligosaccharide aldonic acid and water has been found to have moisturizing, soothing, healing and slow-release effects in addition to other various beneficial effects to skin, mucous membrane, hair and nail. The beneficial effects from an oligosaccharaide aldonic acid within the skin, nail and hair are expected to include those provided by glycosaminoglycans (GAGs). This is due to similarities in the basic chemical structure of oligosaccharaide aldonic acids and GAGs, and the fact that they both form a gel matrix with water. Exemplary beneficial effects and functions of GAGs inside the skin includes (i) binding with polycations and cations, such as sodium and potassium ions, to enhance water retention, and (ii) specific interaction with collagen, elastin, fibronectin, laminin and other proteins to stabilize the turgor of the skin.
3. General Preparation of the Cosmetic and Therapeutic Compositions
(i) General Preparation
Compositions comprising an oligosaccharide aldonic acid or related compound of the instant invention may be formulated as solution, gel, lotion, cream, ointment, shampoo, spray, stick, powder, masque, mouth rinse or wash, vaginal gel or preparation, or other form acceptable for use on skin, nail, hair, oral mucosa, vaginal mucosa, mouth or gums.
To prepare a solution composition, at least one oligosaccharide aldonic acid or related compound of the instant invention is dissolved in a solution prepared from water, ethanol, propylene glycol, butylene glycol, and/or other topically acceptable vehicle. The concentration of a single oligosaccharide aldonic acids or related compound or the total concentration of all oligosaccharide aldonic acids and related compounds, where the composition comprises more than one oligosaccharide aldonic acids or related compounds, may range from 0.01 to 99.9% by weight of the total composition, with preferred concentration of from 0.1 to 50% by weight of the total composition and with more preferred concentration of from 0.5 to 25% by weight of the total composition. Contemplated embodiments of the instant invention include ranges of 0.1% to 0.2%, 0.2% to 0.3%, 0.3% to 0.4%, 0.4% to 0.5%, 0.5% to 0.6%, 0.6% to 0.7%, 0.7% to 0.8%, 0.8% to 0.9%, 0.9% to 1%, 1% to 2%, 2% to 3%, 3% to 4%, 4% to 5%, 5% to 6%, 6% to 7%, 7% to 8%, 8% to 9%, 9% to 10%, 10% to 14%, 14% to 18%, 18% to 22%, 22% to 26%, 26% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% n to 90%, and 90% to 99.9% by weight of the total composition.
To prepare a topical composition in lotion, cream or ointment form, the oligosaccharide aldonic acid or related compounds is first dissolved in water, ethanol, propylene glycol, and/or another vehicle, and the solution thus obtained is mixed with a desired base or pharmaceutically acceptable vehicle to make lotion, cream or ointment. Concentrations of the oligosaccharide aldonic acid or related compounds are the same as described above.
A topical composition of the instant invention may also be formulated in a gel or shampoo form. A typical gel composition is formulated by the addition of a gelling agent such as chitosan, methyl cellulose, ethyl cellulose, polyvinyl alcohol, polyquaterniums, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbomer or ammoniated glycyrrhizinate to a solution comprising the oligosaccharide aldonic acid or related compound. The preferred concentration of the gelling agent may range from 0.1 to 4 percent by weight of the total composition. In the preparation of shampoo, the oligosaccharide aldonic acids or related compounds is first dissolved in water or propylene glycol, and the solution thus obtained is mixed with a shampoo base. Concentrations of the oligosaccharide aldonic acids or related compounds used in gel or shampoo form are the same as described above.
To prepare a combination composition for synergetic effects, a cosmetic, pharmaceutical or other topical agent is incorporated into any one of the above compositions by dissolving or mixing the agent into the formulation.
Other forms of compositions for delivery of oligosaccharide aldonic acids and related compounds of the instant invention are readily blended, prepared or formulated by those skilled in the art.
(ii) Gel Matrix Preparations
In contrast to an alpha hydroxyacid and polyhydroxyacid, an oligosaccharide aldonic acid can form a gel matrix. A gel matrix may be formed on the skin, hair, nail or mucosa when a solution comprising an oligosaccharide aldonic acid undergoes evaporation.
In one example, a gel matrix can be formed when aqueous solution comprising an oligosaccharide aldonic acid is evaporated at room temperature. The transparent gel thus obtained retains certain amount of water forming a clear gel matrix. The amount of water retention depends on individual oligosaccharide aldonic acid. For example, maltobionic acid 1 g in a beaker was dissolved in water 1 ml, and the solution thus obtained was left at room temperature. Fifty percent of the original water had been evaporated at the end of 24 hours, and 57% at the end of 48 hours, and 60% at the end of 72 hours, and no more or minimal evaporation of water could be detected after 72 hours. A clear gel film thus obtained contained 29% water complexed with maltobionic acid molecules. In the same manner, lactobionic acid formed a clear gel matrix with 14% water molecules and cellobionic acid formed a transparent gel with 7% water molecules. The formation of a gel matrix between an oligosaccharide aldonic acid and water has been found to have soothing, healing and slow-release effects in addition to other various beneficial effects to skin, mucous membrane, hair and nail.
The following are illustrative examples of formulations and other aspects of the present invention. Although the examples utilize only selected compounds and formulations, it should be understood that the following examples are illustrative and not limiting. Therefore, any of the aforementioned oligosaccharide aldonic acids or related compounds may be substituted according to the teachings of this invention in the following examples.